Mechanisms of Wnt8 function in zebrafish mesoderm patterning

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Abstract

In vertebrate embryonic development, correct specification of tissue fates along the
dorsoventral (D/V) axis is known to require the secreted signaling ligand Wnt8. Wnt8
signaling promotes ventral fates and antagonizes the expansion of the dorsal domain
known as the organizer. Maintenance of the organizer is critical for proper development
as this tissue is known to produce inhibitors of Wnt and BMP (Bone Morphogenetic
Protein) family ligands; BMPs are also known to play a major role in promoting ventral
fates. In order to understand how Wnt8 antagonizes the organizer, we analyzed the
epistatic relationship between Wnt8 and the transcriptional repressors Vent and Vox
using zebrafish as a model organism. We found that Wnt8/&#946;-catenin signaling directly
regulates the transcriptional levels of vent and vox so that they can repress the
transcription of dorsal genes on the ventral side of the embryo. To understand the
contribution of Wnt8 towards ventral fate specification, we carefully analyzed its
relationship with BMP signaling during gastrula stages. We found that bmp expression
in the mesoderm is under the control of Wnt8 at mid-gastrulation and that regulation of
bmp explains many of the ventral defects observed in wnt8 mutants. Antagonism of the
expression of organizer-derived BMP inhibitors by Wnt8 also indirectly allows timely
BMP signaling. Analysis of wnt8; bmp double mutants revealed an early unsuspected
function of BMP in the antagonism of the organizer. Further, we uncovered a
mechanism through which regulation of vent, vox and a related-gene ved expression by
both Wnt8 and BMP antagonizes dorsal/axial mesoderm identity to preserve the integrity
of ventral/non-axial tissues. In summary, we have revealed some of the mechanisms of
Wnt8 function in D/V mesoderm patterning: it restricts the organizer domain by
regulating vent and vox, it allows BMP induced differentiation through its inhibition of
BMP antagonists derived from the organizer and it co-regulates vent, vox, and ved with
BMP signaling to allow maintenance of the non-axial domain.